In recent years, a measure to enhance virus safety has been necessary for not only plasma derivatives derived from human blood, but also bio-pharmaceuticals. Therefore, pharmaceutical manufacturers have studied to introduce a virus removal/inactivation step in a manufacturing process. In particular, a virus removal method by filtration with a virus removal membrane is an effective method that can provide virus reduction without denaturing a useful protein.
Among viruses, in particular, parvovirus has been reported with respect to a case of infection with human parvovirus B19 in the field of plasma derivatives, and a case of contamination of CHO (Chinese Hamster Ovary) cells with mouse parvovirus in the bio-pharmaceutical field. Parvovirus, which is a small virus, has no envelope, and it is thus physicochemically stable and is resistant to heating, a low pH and a treatment with a chemical agent which correspond to an inactivation step generally performed during a pharmaceutical manufacturing process. Therefore, there is a growing need for parvovirus removal by a virus removal membrane, as a virus removal method having a different mechanism from that of an inactivation method.
For example, Patent Literature 1 discloses a polymer porous hollow fiber membrane having a pore structure in which the in-plane porosity is first decreased from the inner wall surface of the membrane towards the wall inside thereof, then takes at least one local minimum value, and is thereafter increased at the outer wall portion thereof (hereinafter, also referred to as “gradient structure”), as well as a virus removal method including filtering an aqueous protein solution by use of the membrane. The virus removal membrane having such a gradient structure and having a specific average pore size is considered to be suitable for virus removal at a high removal rate and protein recovery at a high permeation efficiency without denaturing a protein, in virus removal from an aqueous protein solution. The virus removal membrane exhibits removal property of viruses having a medium size (35 nm to 55 nm), but it can ensure no virus removal property of small viruses (parvovirus and the like).
Patent Literature 2 discloses a method of producing a hollow fiber membrane that can achieve a high virus removal property, and this method involves coagulation of a cuprammonium cellulose solution in a U-tube to suppress, as much as possible, of structural disorder due to stretching during structure formation of microphase separation. The method is effective for removal of viruses having a medium size (JEV), but it can ensure no sufficient removal property of small viruses.
Patent Literature 3 discloses removal of a parvovirus as a small virus by adjustment of the ratio (BP/γ) of the bubble point BP (MPa) to the surface tension γ (N/m) of a virus removal membrane.
Patent Literature 4 discloses characteristic evaluation of a virus removal membrane, which is performed using viruses and proteins. This Literature describes staining viruses and proteins by a fluorescent dye, and a membrane structure necessary for high virus removal performance and protein permeability. No sufficient studies, however, have been made about conditions for ensuring virus removal property, and no studies have been made for enhancements in filtration efficiencies (filtration throughput and filtration rate).